Hidden in plain sight: chlamydial gastrointestinal infection and its relevance to persistence in human genital infection

Abstract

Although the concept of persistence in chlamydial infections has been recognized for about 80 years, there is still very little known about the mechanism by which this occurs. In this review, we revisit an old paradigm, long known to chlamydiologists and veterinarians, that in virtually all hosts of chlamydiae, including mammals and birds, chlamydiae reside in the gastrointestinal tract for long periods of time in the absence of clinical disease. Thus, if gastrointestinal infection occurs in most hosts, then it is very likely that gastrointestinal infection occurs in humans as well. We demonstrate that gastrointestinal infection does indeed occur in humans and propose that this anatomical site is the source of persistent infection in humans. The data in ruminants and animal models demonstrate that the immune system is unable to clear chlamydiae from the gut, so they can remain indefinitely, with continual shedding in feces. Clearly, many women become reinfected from an untreated partner; however, we propose that women, cured of genital infection, remain at risk for autoinoculation from the lower gastrointestinal tract. Moreover, there are substantial data demonstrating treatment failure of chlamydial infections, particularly with azithromycin. New data in the mouse model have shown that azithromycin is far less effective against chlamydial gastrointestinal infection than against genital infections. Therefore, it is possible that women cured of genital infection by antibiotics remain infected in the gastrointestinal tract and can become reinfected by autoinoculation from that site.

Figures

FIG 1

When mice are infected with C. muridarum orally and intravaginally, chlamydial infection is established in both the cervix and cecum. An immune response is elicited in both sites; however, only the cervical infection resolves. It is suggested that downregulatory mechanisms operative in the cecum prevent the adaptive immune response from resolving the infection, allowing the infection to persist indefinitely. As evidence of downregulatory mechanisms in the cecum, no inflammatory response is seen in histopathological examination of the tissue. In contrast, a robust inflammatory response develops in the cervix within 24 h of infection and does not resolve until the organism is cleared by the adaptive immune response.

FIG 2

Depiction of proposed transmission patterns in humans. Sexual transmission occurs between men and women, but oral infection may also occur via oral sex or mechanical transmission. Oral infection may result in clinical or subclinical pharyngitis, and the organisms may pass through the GI tract to the large intestine and rectum, where they can be shed. If the infection persists in the lower GI tract as it does in most animals, there is a risk of autoinfection in the female even when chlamydial infection in the genital tract has been cleared via the immune response or antibiotic therapy. It is also possible that treatment by the use of an antibiotic, particularly azithromycin, is more effective in curing genital infection than GI infection, considering the relatively high incidence of treatment failure in rectal infections.